A number of disease states including
WHIM syndrome,
HIV infection and
cancer have been linked to the
chemokine receptor CXCR4. High-affinity CXCR4 antagonist transition
metal complexes of configurationally restricted bis-tetraazamacrocyclic
ligands have been identified in previous studies. Recently synthesised and structurally characterised Co2+/Co3+ and Ni2+
acetate complexes of mono-macrocycle cross-bridged
ligands have been used to mimic their known coordination interaction with the
aspartate side chains on binding to CXCR4. Here, X-ray crystal structures for three Co2+/Co3+
acetate complexes and five Ni2+
acetate complexes are presented and demonstrate flexibility in the mode of binding to the
acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Complexes of the smaller Co3+
metal ion exclusively bind
acetate by chelating both oxygens of
acetate. Larger Co2+ and Ni2+
metal ions in cross-bridged
tetraazamacrocycles show a clear tendency to coordinate
acetate in a monodentate fashion with a coordinated water molecule completing the octahedral coordination sphere. However, in unbridged tetraazamacrocycle
acetate structures reported in the literature, the coordination preference is to chelate both
acetate oxygens. We conclude that the short
ethylene cross-bridge restricts the equatorial bulk of the macrocycle, prompting the
metal ion to fill the equator with the larger monodentate
acetate plus water
ligand set. In unbridged
ligand examples, the flexible macrocycle expands equatorially and generally only allows chelation of the sterically smaller
acetate alone. These results provide insight for generation of optimised bis-macrocyclic CXCR4 antagonists utilising
cobalt and
nickel ions.